Neuropeptide Y (NPY) is a 36 amino-acid peptide which co-exists with norepinephrine (NE) in sympathetic postganglionic nerves innervating the cardiovascular system and in platelets. NPY causes vasoconstriction when infused into the systemic circulation. Our previous studies have determined that NPY-immunoreactivity (-ir) is released from both these sources and that the magnitude and pattern of NPY release differed from that of NE. To study the kinetics of NPY release from sympathoneural terminals, left renal nerves were stimulated in adrenal-demedullated anesthetized rats. Significant, frequency-dependent increases in renal spillover of NE were accompanied by moderate (25-30%) elevations in renal venous NPY-ir (authenticity confirmed by HPLC) which were independent of frequency or mode of stimulation. There was no renal extraction of NPY as assessed by extraction of [125-I]NPY. In conscious rats, stress of immobilization which increased plasma catecholamine levels, failed to elevate plasma NPY-ir, however, clearance of NPY increased. In contrast, in adrenal-demedullated rats immobilization evoked marked increases of plasma NPY-ir without affecting NPY clearance, indicating that sympathoneuronal release of NPY increased. Adrenal medulla (or adrenaline) seems to play a role in plasma clearance of NPY during stress but is insignificant as a source of NPY released into circulation. NPY exerts multiple bioactivities in the rat cardiovascular system: 1/ vasoconstriction and potentiation of NE actions (Y1 receptors, primary action); 2/ vasodilation via histamine release from mast cells and inhibition of NE release (Y2 receptors, secondary actions); 3/ potentiation of collagen-induced platelet aggregation (Y2 ?, inhibition of adenyl cyclase), and 4/ stimulation of proliferation of vascular smooth muscle cells in culture. Thus, NPY may be released from sympathetic nerves and platelets in states such as stress and influence vascular and platelet actions and interactions promoting vasoconstriction, thrombosis and vascular growth. Using specific NPY antagonists which will be available soon, we will be able to determine whether these actions of NPY contribute to vascular derangements in experimental models of hypertension and chronic stress.